Interleukin-6

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Interleukin-6
Interleukin-6
Belt model according to PDB  1ALU

Existing structural data : 1alu , 1il6 , 1n2q , 1plm , 2il6

Properties of human protein
Mass / length primary structure 185 amino acids
Identifier
Gene name IL6
External IDs
Occurrence
Homology family IL6
Parent taxon Amniotes

Interleukin-6 (short: IL-6 , synonymous older names: Interferon-β2 ( IFNB2 ), B-cell-stimulating factor , B-cell differentiation factor , liver cell-stimulating factor ) belongs to the interleukins (or more comprehensive the cytokines ), which regulate the inflammatory response of the organism. Due to the nature of its complex regulation and functions in the orchestra of other cytokines and cells, IL-6 plays a key role in the transition from mechanisms of innate immunity to mechanisms of acquired immunity within the inflammatory process. IL-6 belongs to a family of cytokines that share the glycoprotein gp130 receptor subunit . The multifunctionality of cytokines is often incorrectly referred to as pleiotropy (pharmacology) ; however, this term should not be used in this context.

Genetics, Education and Secretion

In humans, IL-6 is encoded on chromosome 7 gene locus p21. The gene segment contains 5 exons . An inactive precursor protein , which consists of 212 amino acids, is transcribed . The transcription is induced , among other things, by the transcription factors NF-κB , NF-AT , HSF1 and HSF2 .

The 184 amino acid long active interleukin-6 is split off from the precursor protein. Various isoforms are generated post-translationally (via cleavage of peptides, glycosylation , phosphorylation ), the biological significance of which has not yet been clarified.

The circulating IL-6 is excreted by the liver and kidneys , the half-life in the serum is in the range of minutes.

The formation of interleukin-6 is increased by prostaglandin-E2 .

Regulation of the interleukin-6 effect

As an activating ligand, interleukin-6 can bind to two types of receptors:

  1. to a membrane-bound IL-6 receptor (IL-6R), which is only found on liver cells and leukocytes and transmits its signals with the aid of the receptor-associated, signal-transducing glycoprotein gp130 ,
  2. to a soluble IL-6 receptor (sIL-6R). The resulting IL-6 / sIL-6R complex binds to the glycoprotein gp130, which is the only one found in cell membranes of many cell types, and activates it. This second process is called "IL-6 trans -signaling". It is important for the numerous cells that express gp130 (which occurs ubiquitously) but not IL-6R on their cell surface. IL-6 trans signaling is inhibited by naturally occurring soluble sgp130, which inactivates the IL-6 / sIL-6R complex, but not IL-6 alone and its effect on the membrane-bound IL-6 receptor.

These two possible effects provide many starting points for a differentiated regulation of the IL-6 effect:

  1. Regulation of IL-6 itself;
  2. Regulation of sIL-6R: sIL-6R occurs in the serum of healthy people at a concentration of 25–35 ng / ml and this level increases significantly in various diseases such as a. Rheumatism , AIDS or certain forms of leukemia . In principle, sIL-6R can arise either by splitting off the extracellular part of the membrane-bound IL-6R (on leukocytes and liver cells) or by special splicing during the intracellular formation of IL-6R. The former is z. B. triggered by C-reactive protein or by certain bacterial toxins. The latter is z. B. stimulated by Oncostatin-M .
  3. Regulation of the soluble glycoprotein gp130.

Functions

When the glycoprotein Gp130 is activated by an IL-6 / sIL-6R complex or when an IL-6R (to which gp130 is associated) is activated by IL-6, a Janus-activated kinase at its domain inside the cell becomes a tyrosine phosphorylated , whereby the JAK-STAT signaling pathway and the MAP kinase pathway are activated, which then leads to the transcription of certain target genes in the cell nucleus.

Traditionally, interleukin-6 is considered to be an activator of acute phase proteins and a factor that stimulates lymphocytes .

Inflammatory response

In an acute inflammatory episode, neutrophils are first recruited, which infiltrate the inflammatory focus, then do their work there, die off quite quickly and are then replaced by a longer-lasting population of more specific inflammatory cells such as lymphocytes and mononuclear cells . The interleukin-6 effectiveness plays an important role here: with the degree of infiltration by neutrophils, the local concentration of sIL-6R increases, which triggers IL-6 trans signaling in the surrounding tissue. This in turn limits the accumulation of neutrophil granulocytes in the inflamed tissue in various ways. At the same time, the IL-6 trans -signaling attracts CD3 + T lymphocytes, which marks the transition from the innate immune response to a learned immune response. Furthermore, IL-6 is involved in the regulation of leukocyte apoptosis with pro-apoptotic and anti-apoptotic active components (of which it is not yet known how they are balanced). IL-6 has an antiapoptotic effect on resting and activated T lymphocytes, and it regulates their differentiation, proliferation , polarization and the immunoglobulin G secretion of B lymphocytes. In the case of activated T lymphocytes in particular, soluble sIL-6R is necessary to mediate these effects, because activated T lymphocytes usually do not have any membrane-bound IL-6 receptors. Monocytes are differentiated more into macrophages by IL-6 .

Effect on hormone secretion

IL-6 increases the secretion of cortisone , somatotropin , glucagon and adrenaline (in descending order) .

Regulation of interleukin-6 through muscle strain

Interleukin-6 is secreted about 100 times more strongly through vigorous muscle strain - especially over a longer period of time (6 hours). The maximum release is found at the end of the muscle exercise. After that, the IL-6 concentration drops quickly again. The IL-6 comes partly from the stressed muscle cells themselves. After longer training, the body adapts to this and secretes less interleukin-6 when the load remains the same as well as during the breaks.

Practical meaning

The concentration of IL-6 in the plasma is approx. 1 pg / ml (or 0.001 ng / ml) in healthy individuals and can increase to 1000 pg / ml (or 1 ng / ml) in severe systemic infections. Less dramatic increases can be found in a number of inflammatory and infectious diseases and (dose-dependent) in muscle exertion. Overall, IL-6 reacts very quickly, its half-life in the serum is in the range of minutes. These properties are used in intensive care medicine for the rapid assessment of acute septic clinical pictures.

A pathogenetic role of IL-6 is discussed in the metabolic syndrome , since a chronically slightly elevated serum IL-6 (around 10 pg / ml) can occur.

Specific antibodies against the IL-6 receptor have been developed to block the effectiveness of IL-6: tocilizumab , an IL-6 receptor antibody which is used in the treatment of certain forms of rheumatism .

Interleukin-6 may offer a new approach in the treatment of Alzheimer's disease . Animal studies have shown that the cytokine can induce the microglia to break down plaques .

IL-6 has also been identified as a possible trigger of the inflammatory reaction in severe courses of acute pancreatitis and is being discussed in combination with other immune markers for the early diagnosis of severe courses of pancreatitis.

Web links

Individual evidence

  1. ↑ a b c Simon A. Jones: Directing Transition from Innate to Acquired Immunity: Defining a Role for IL-6 . In: The Journal of Immunology . tape 175 , no. 6 , 2005, ISSN  0022-1767 , p. 3463-3468 , doi : 10.4049 / jimmunol.175.6.3463 , PMID 16148087 .
  2. ↑ a b Peter C. Heinrich, Iris Behrmann, Serge Haan, Heike M. Hermanns, Gerhard Müller-Newen, Fred Schaper: Principles of interleukin (IL) -6-type cytokine signaling and its regulation . In: Biochemical Journal . tape 374 , no. 1 , 2003, p. 1-20 , doi : 10.1042 / bj20030407 , PMID 12773095 .
  3. ↑ a b c d e C. P. Fischer: Interleukin-6 in acute exercise and training: what is the biological relevance? ( Memento of April 13, 2015 in the Internet Archive ) (PDF; 613 kB) In: Exerc Immunol Rev. Volume 12, 2006, pp. 6–33; PMID 17201070 .
  4. ↑ SA Jones, et al .: C-reactive Protein: A Physiological Activator of Interleukin-6 Receptor Shedding. In: Journal of Experimental Medicine . 189, 1999, pp. 599-604 ( jem.org PDF).
  5. ↑ Paramita Chakrabarty, Karen Jansen-West, Amanda Beccard, Carolina Ceballos-Diaz, Yona Levites, Christophe Verbeeck, Abba C. Zubair, Dennis Dickson, Todd E. Golde, Pritam Das: Massive gliosis induced by interleukin-6 suppresses Abeta deposition in vivo: evidence against inflammation as a driving force for amyloid deposition . In: FASEB Journal . tape 24 , no. 2 , February 2010, ISSN  1530-6860 , p. 548–559 , doi : 10.1096 / fj.09-141754 , PMID 19825975 , PMC 3083918 (free full text).
  6. ↑ Z. Dambrauskas, N. Giese, A. Gulbinas, T. Giese, PO Berberat, J. Pundzius, G. Barauskas, H. Friess: Different profiles of cytokine expression during mild and severe acute pancreatitis. In: World J. Gastroenterol. 16, 2010, pp. 1845-1853 PMID 20397261 PMC 285682 (free full text).